One of the main characteristics of multiple sclerosis (MS) is the
existence of a 'clinico-radiological paradox'. The
discrepancies observed between the clinical and radiological findings
might be partly attributable to lack of specificity of the imaging
measures, but also to functional reorganization mechanisms occurring at
both the brain and spinal cord levels. These neuroplastic processes
might provide a means of delaying the clinical expression of some
functional symptoms. Functional MRI (fMRI) methods provide a useful
means of determining whether functional reorganization mechanisms of
this kind are at work. It has been established, for example, that these
neuroplastic mechanisms occur right from the start of the disease and
may contribute to reducing the expression of the symptoms resulting from
pathological tissue damage. This functional reorganization may therefore
constitute an important adaptive mechanism during the early stages of
the disease. One potential practical application of the findings made on
these neuroplastic processes is likely to be the development of specific
rehabilitation methods, which can be used to enhance these reactive
mechanisms in order to maintain MS patients' functional abilities,
and other specifically targeted approaches will also predictably be
developed.

Multiple sclerosis (MS) is characterized by the fact that although
the evolution of the disease is often unpredictable, the temporal and
spatial dynamics play a particularly important role. The so-called
'clinico-radiological paradox' whereby the pathological
lesions are associated with only weak clinical symptoms although
considerable changes are detected at MRI level, might be attributable to
various factors inherent to the disease, such as the fact that some of
the lesions located in non-functional territories are
'silent', the occurrence of spontaneous repair and/or
remyelination processes in patients with inflammatory lesions, and/or
ion channel redistribution mechanisms.

The lack of specificity of the imaging measures, and in particular,
the pathological heterogeneity of T2-visible MRI lesions, could also be
in part an explanation for the MS clinico-radiological paradox. In
addition, the existence of neuroplastic mechanisms reflecting the
plasticity of the adult human brain has been amply documented during the
past few years. This functional brain plasticity may be mediated by
various processes, such as cell renewal, remyelination, neurite
extension, new synapse formation, ion channel redistribution and
cortical reorganization processes involving the main associative
pathways. The neuroplastic processes occurring in response to
pathological lesions may reduce the functional consequences of these
lesions and thus prevent or reduce the clinical expression of the
symptoms. It was recently suggested, on the basis of fMRI studies, that
cortical reorganization processes of this kind might prevent the
expression of acute symptoms (relapses) and slow down the gradual
aggravation of the natural evolution of the disease.

fMRI Studies on MS

The processes observed using fMRI methods result from local
variations in the cerebral blood oxygen levels and blood flow triggered
by the activation of the cortical regions associated with the
performance of specific tasks. Haemoglobin, the magnetic properties of
which depend on its oxidation state, constitutes a useful endogenous
contrast product. In the cortical regions activated, the partial oxygen
blood pressure decreases the deoxyhaemoglobin levels, thus reducing the
local magnetic field measured using MRI methods, which makes it possible
to detect any changes in the signals occurring in the zones involved
(this is the BOLD effect: the Blood Oxygen Level Dependent contrast
effect). The changes in cortical activity resulting from the performance
of a motor, cognitive or visual task can be detected by comparing the
difference between the signal observed on MRI during the activation
phase and the resting phase (which is known as the blocked mode).
Statistical analyses can be carried out in order to determine the
cortical regions where the signal differs significantly between the
resting and activation phases, and the statistical map thus obtained can
be superimposed on an anatomical image in order to determine exactly
which regions have been activated.

fMRI methods therefore undeniably constitute a valuable means of
studying the functional brain reorganization occurring secondary to MS
lesions: this method makes it possible to establish correlations between
the extent of pathological processes and the corresponding patterns of
brain activation, and thus to assess the functional benefits of this
cerebral plasticity.

fMRI and Plasticity in MS fMRI and Motor and Sensory Tasks

Several authors have shown that the regions activated in patients
with remittent or primary progressive forms of MS performing motor tasks
were the classical motor regions as well as multimodal cortical regions
which are normally not activated during the performance of tasks of this
kind. (1,2) This finding suggests that the mechanisms responsible for
functional reorganization involve not only the recruitment of vicarious
motor circuits, but also more complex processes. In particular, it was
recently reported that functional cortical reorganization processes
occurred during the initial stage of the disease (clinically isolated
syndrome [CIS]), since a greater and more diffuse level of activation
occurred in patients than in the control subjects in both the contra-
and ipsilateral motor cortex, although both populations achieved similar
motor performances. (3) At this stage of the disease, the plasticity of
the brain may therefore contribute to maintaining normal motor
performances despite the presence of tissue lesions. These findings
clearly suggest that a compensatory process intervenes at an early stage
of the disease in the patients' motor system. (4) The patterns of
activation detected in the cortical regions of patients but not in
control subjects during the performance of simple motor tasks may have
resulted from the fact that brain networks normally mediating more
complex motor tasks were recruited. (5) One of the main principles
underlying the compensatory reorganization processes occurring in
patients with pathological lesions and enabling them to perform simple
tasks as efficiently as normal subjects may therefore involve the
recruitment of brain systems normally devoted to complex activities.
This hypothesis would at least partly account for the feeling expressed
by the patients tested that considerable mental efforts were required to
perform a simple task. Similar findings have been made on CIS patients,
in whom networks normally involved in the performance of complex motor
tasks were recruited while simpler tasks were being performed. These
findings suggest that neuroplastic mechanisms occurring in the very
early stages of the disease may prevent or delay the clinical expression
of the patients' motor impairments. This functional reorganization
may vary, depending on the clinical form of the disease and its time
course. These neuroplastic processes might be particularly effective in
young patients with only slight disabilities and weak diffuse structural
damage, and became weaker with the extent of the disabilities and the
aggravation of the structural diffuse changes. (7,8) The functional
reorganization detected using fMRI methods does not actually seem to be
restricted to the brain, since authors using this method recently
observed changes in the patterns of activation recorded in the cervical
medulla in response to proprioceptive stimulation, which might also
contribute to reducing the clinical consequences of pathological tissue
lesions. (9,10)

fMRI and Cognitive Tasks

The question of whether cerebral plasticity, which may reduce the
clinical repercussions of pathological processes in the case of motor
activities, might also apply to more complex functions has been raised.
Recent studies on brain network reorganization during the performance of
complex cognitive tasks have shown that the patterns of cortical
activation recorded in the prefrontal and parietal regions and the
anterior cingulate cortex differed from those recorded in the control
group. (11-13) The various patterns of cortical activation recorded
suggest the occurrence of complex processes of reorganization involving
both the working memory and brain regions which are not normally
recruited during the performance of tasks of this kind. The authors of
recent studies using PASAT procedures on patients in the early stage of
CIS established that compensatory functional cortical processes
contributed to complex information processing operations in these
patients. (14,15) Changes in cortical activation patterns have also been
observed in patients whose performances did not differ from those of
control subjects. The changes observed are both quantitative (greater
levels of activation have been recorded in the right and left prefrontal
cortices of patients than in control subjects) and topographic (the
right fronto-polar cortex and the right cerebellar hemisphere were found
to be involved) (Figure 1). Some more specific studies have also been
performed using effective and functional connectivity methods to detect
changes in the functional connections between various cortical regions
involved in complex information processing. The results obtained have
shown a functional connectivity decrease and a modulation of effective
connectivity between the cortical areas involved in the working memory
system. (16,17) These processes of reorganization may therefore play a
compensatory role by reducing the cognitive effects of the pathological
processes, thus considerably masking the functional repercussions of the
tissue lesions occurring in the early stages of the disease. Several
factors might contribute to the existence and the extent of these
adaptive functional mechanisms. First of all, the presence of severe
cognitive deficits predominating at the attentional level might be a
factor inhibiting neuroplasticity. (18) Secondly, the compensatory
mechanisms might depend on the clinical form of the disease. (19) Last
but not least, the patients' level of education (their
'cognitive reserves') might contribute decisively to the
development of compensatory functional reorganization processes. (20,21)

[FIGURE 1 OMITTED]

Morphological, Structural and Metabolic Correlates of Brain
Plasticity in MS

A number of studies have shown the existence of significant
correlations between the occurrence of cortical reorganization and the
lesion load assessed on T2-weighted sequences. However, the diffuse
damage undergone by the cerebral parenchyma (especially in the normal
appearing white matter [NAWM]) was found to be a more related to
cortical reorganization than the lesion load or the topographical
distribution of the lesions. The enhanced recruitment of the cortical
regions involved in the performance of motor tasks was found to be
significantly associated with diffuse tissue damage, as assessed using
magnetization transfer and diffusion imaging methods and based on the
decreased levels of N-Acetyl Aspartate (a marker of axonal dysfunction)
using MR spectroscopy imaging. (22) Likewise, quantification of the
overall tissue damage has made it possible to assess the functional
effects of diffuse white matter tissue damage on the functional
reorganization mechanisms occurring in the earliest stage of the
disease, using methods based on cognitive tasks (Figure 2). (23,24)
Interestingly, using perfusion MRI, recent studies have shown a
decreased perfusion of the NAWM that might be caused by a widespread
astrocyte dysfunction. (25) Early diffuse brain damage might therefore
trigger these recruited functional reorganization processes preventing
the clinical expression of the symptoms of the disease. (26) MS may also
involve functional changes in the connections involved in the activation
of the cortical regions associated with the motor and cognitive
abilities tested. (15,16,27,28) Lastly, this functional plasticity might
be partly mediated by structural changes in the associative pathways
involved in the functional reorganization processes, since it was
recently reported by authors using a diffusion tensor tractography
imaging approach that the number of connections between some brain
regions was higher in MS patients than in control subjects, which
suggests that the white matter was endowed with reactive structural
plasticity. (29)

[FIGURE 2 OMITTED]

Conclusion

The finding that neuroplastic processes may reduce the clinical
expression of some symptoms, such as motor disorders and cognitive
deficits, during the early stages of MS should make it possible in the
near future to develop rehabilitation strategies based on specific
training designed to enhance these potential compensatory mechanisms and
thus to maintain the patients' functional performances by
preventing or reducing the clinical expression of the disease. (30,31)
In addition, the functional reorganization processes recently found to
occur suggest that a targeted therapeutic approach could be developed to
deal with these symptoms, on similar lines to what has been done in the
framework of some cognitive disturbances. (32) Further information is
still required, however, about the mechanisms underlying this functional
reorganization and their morphological, structural and metabolic
correlates. For this purpose, longitudinal studies will have to be
carried out to determine how these compensatory processes evolve with
time, and to establish in particular what the limiting factors may be,
such as the thresholds beyond which these processes may no longer be
effective (Figure 3). (33,34) Despite technical problems affecting fMRI
data acquisition and analysis which still remain to be solved,
multicentre studies on the use of this approach should definitely be
envisaged. (35)

[FIGURE 3 OMITTED]

Key Points

* fMRI studies have recently established that neuroplastic
processes occur in patients with MS

* These compensatory functional reorganization processes, which
have been found to occur in the very earliest stages of the disease, may
limit the clinical expression of some of the symptoms of the disease

* The diffuse structural and metabolic damage detected using
non-conventional MRI methods have been found to contribute more
decisively to explain these neuroplastic processes than the topographic
distribution of the macroscopically identified lesions or the extent of
these lesions

* In the early stages of the disease, these compensatory mechanisms
may largely mask the functional effects of tissue lesions, which are
often fairly slight at this stage, but as the symptoms evolve,
neuroplastic mechanisms may no longer suffice to compensate for the
increasingly severe structural lesions, and the functional symptoms
therefore begin to show up

* Longitudinal studies would help to explain why these compensatory
functional processes are liable to be limited, as well as providing
information which could be used to develop specific rehabilitation
methods for enhancing these reorganizational processes and thus delaying
the onset of the functional symptoms in patients with early MS